The investigator is a senior resident in Clinical Pathology Training at Northwestern University Medical School, who will be board-eligible in the spring of year 2000. He will join the Department of Pathology as Assistant Professor, tenure-eligible Investigator-Clinician track, beginning April 1, 2000, to develop an independent hypothesis driven basic research program focusing on the role of nuclear receptor coactivators in development, differentiation and neoplastic conversion in breast induced by natural and synthetic ligands of nuclear receptors. Northwestern University provides an excellent environment for research dealing with nuclear receptors, transcription factors, and nuclear receptor coactivators on the responses of genes, cells, tissues, and species to the influence of natural and synthetic agonists and antagonists. Strong programs in molecular mechanisms of xenobiotic mediated transcriptional activation of genes exist with nationally recognized leaders dealing with: peroxisome proliferators (Drs. J. K. Reddy, T. Hashimoto, and M. S. Rao), responses of cells to environmental stress and altered gene products (Dr. R. Morimoto), molecular mechanisms of copper, mercury and other trace metal toxicity and the role of metallochaperones (Dr. T. O'Halloran), transcriptional corepressors and coactivators (thyroid and estrogen receptor action, Dr. L. Jameson; mitochondrial gene regulation, Dr. R. Scarpulla; and coactivators in cell cycle regulation Dr. B. Thimmapaya), and prevention of breast cancer using antiestrogens tamoxifen and raloxifene (Dr. C. Jordan). Some of these individuals also serve as preceptors on the pre- and postdoctoral Molecular Toxicology Training Program (NIEHS) at Northwestern University. The goal of the mentored Clinical Scientist Development Program is to fully train Dr. Yijun Zhu in an integrated and highly interactive atmosphere in the area of molecular mechanisms responsible for gene expression and in exploring the relevance of single and multiple gene defects in the overall phenotypic outcome by developing transgenic and gene knockout mice. The proposed training program will enable the candidate to enhance his scientific foundation of critical thinking and experimentation. He will also acquire the skills necessary to effectively and intensely interface in the clinical pathology laboratories, in a subspecialty diagnostics area in a major academic medical center. The proposed research focuses on the role of PBP, a peroxisome proliferator activated receptor--binding protein, in breast development and neoplastic conversion. Dr. Zhu cloned PBP, identified it as a nuclear receptor coactivator and found that it is amplified and overexpressed in some human breast cancers. Since a variety of phytoestrogens and environmental endocrine disrupting chemicals possess estrogen receptor activity, exploration of interactions of PBP with estrogen receptor and p53 and the development of transgenic models of overexpression of PBP and the gene disruption model of PBP deficiency will provide fundamental clues as to the role of coactivators in development, differentiation and neoplastic conversion.